Since the discovery of insulin by Banting and Best, regular insulin injections have remained the best and most frequently used therapy to control abnormal blood glucose levels in diabetic patients (Pierce et al in Heart Dysfunction in Diabetes (CRC Press: Boca Raton, Fla., 1988). The use of insulin has significantly prolonged the life of diabetic patients and reduced the severity of many complications associated with this disease. Besides insulin, only the sulfonylurea drugs have gained widespread use for the control of diabetes (Pierce et al, 1988).
Despite the acceptance of insulin and sulfonylurea drugs as effective therapies, there are significant limitations inherent in their use. For example, sulfonylurea drugs are usually used only in cases of mild diabetes. Furthermore, insulin injections, although effective, are not an optimum way of controlling the disease. This is due to the fact that daily injections with needles is painful and unpleasant. Unfortunately, other means of delivering insulin, for example, implanted mini-pumps and islet transplantation, have not evolved to a point where they could be considered viable replacements for daily injections of insulin (Pierce et al, 1988).
As a consequence, there has been considerable effort expended searching for insulin-mimetic compounds. For example, vanadate was identified over 10 years ago as a replacement for insulin (Heyliger et al, 1985, Science 227: 1474). Therein, vanadate was shown to control diabetes in an insulin-deficient, streptozotocin-induced rat model of diabetes (Heyliger et al, 1985). Specifically, vanadate was included in the drinking water of the rats, thus removing the need for unpleasant injections (Heyliger et al, 1985). However, there were three important limitations in this methodology: first, the animals began to stop drinking the water containing vanadate; second, it was difficult to regulate and quantitate the amount of vanadate being administered to the rats in this manner; and third, and most importantly, the animals developed a life-threatening diarrhea when the vanadate was administered in this manner. Other complications accompanying the severe diarrhea included weight loss, depressed appetite, neurological disorders, liver cytotoxicity and death (Mongold et al, 1990, Pharm Tox 67: 192-198; Domingo et al, 1995, Mol Cell Bio 153: 233-240; Malabu et al, 1994, Diabetes 43: 9-15; Llobet and Domingo, 1984, Tox Letters 23: 227-231; Domingo et al, Pharm Tox 68: 249-253).
Thus, although vanadate was considered a potentially important therapy for controlling diabetes, the side-effects associated with its administration have been so serious as to preclude any clinical use.
Some laboratories have attempted to circumvent the gastrointestinal complications by developing vanadate analogues (Aharon et al, 1998, Diabetes Care 21: 2194; Halberstam et al, 1996, Diabetes 45: 659-666; Goldfine et al, 1995, J Clin Endocrinol Metab 80: 3312-3320) that would increase the hypoglycemic action while limiting the harmful side effects, that is, the generation of diarrhea. An example is vanadyl sulfate (Aharon et al, 1998). However, to our knowledge, no vanadate analogues have successfully addressed the problem in a manner that would make these compounds useful in a clinical setting. The central problem remains: ingestion of vanadate induces severe diarrhea and other toxic complications (Shechter, 1990, Diabetes 39: 1-5; Mongold et al, 1990; Domingo et al, 1995; Malabu et al, 1994; Llobet and Domingo, 1984; Domingo et al, 1991). However, “the idea of having an insulin-mimetic agent capable of utilizing an alternative pathway is very attractive, as discussed earlier. This is especially true if the substance can be administered orally. Studies should continue to elucidate the level of vanadate toxicity over prolonged treatment and to search for agents that can be coadministered with vanadate and reduce the dosage required to achieve normoglycemia” (Shechter, 1990).
Clearly, a method for orally administering vanadate without the side-effects discussed above is needed. Similarly, an orally-administered pharmaceutical composition for treating diabetes comprising an insulin-mimetic agent such as vanadate and a suitable carrier such that side-effects are minimized is needed.